This document lays out the fiscal year 2009 to 2012 objectives of the U.S. Environmental Protection Agency (EPA), Office of Research and Development (ORD) research program in computational toxicology. Computational toxicology is the application of mathematical and computer models to help assess chemical hazards and risks to human health and the environment. Supported by advances in informatics, high-throughput screening technologies, and systems biology, EPA is developing robust and flexible computational tools that can be applied to the thousands of chemicals in commerce and the contaminant mixtures found in Americas air, water, and hazardous-waste sites. The ORD Computational Toxicology Research Program (CTRP) is composed of three main elements. The largest component is the National Center for Computational Toxicology (NCCT), which was established in 2005 to coordinate research on chemical screening and prioritization, informatics, and systems modeling. The second element consists of related activities in the National Health and Environmental Effects Research Laboratory (NHEERL) and the National Exposure Research Laboratory (NERL). The third and final component consists of academic centers working on various aspects of computational toxicology and funded by the EPA Science to Achieve Results (STAR) program.